Project Summary/Abstract: Candidate/Career Development: This proposal describes a 2-year research program in which the applicant, Dr. Brian Laidlaw, will establish himself as an independent investigator and work towards submitting a competitive application for regular research grant support. Dr. Laidlaw is currently a postdoctoral fellow in the laboratory of Dr. Jason Cyster, a Professor in the Department of Microbiology and Immunology at UCSF and an Investigator of the Howard Hughes Medical Institute. Dr. Cyster has immense experience preparing trainees for positions as independent investigators and is fully committed to providing Dr. Laidlaw with the support needed to successfully transition into a tenure-track position. Dr. Laidlaw will also utilize the extensive career development resources offered at UCSF, including a 16-hour course on Scientific Leadership and Laboratory Management, to strengthen his training in the skills required to successfully manage a research group. Dr. Laidlaw has established a mentorship committee and external collaborations to provide additional guidance on the described project and transition towards independence. In published work, Dr. Laidlaw characterized a population of memory B cell precursor cells residing within the germinal center following viral infection. He currently is using insight gleaned from that study to better understand the transcriptional regulation of memory B cell development and the influence of cell positioning in this process. Dr. Laidlaw will continue to explore the signals regulating memory B cell development as an independent investigator with the long-term goal of leveraging this knowledge in the design of vaccines better able to elicit a protective memory B cell response. Research Proposal: Influenza is an acute respiratory infection that is responsible for up to 650,000 deaths and 3-5 million cases of severe illness worldwide each year. While vaccination can prevent disease, seasonal flu vaccine efficacy ranges from 10-60% resulting in an urgent need to design broadly protective influenza vaccines. Memory B cells in the lungs can provide protection against influenza challenge, with this population possessing an elevated frequency of cross-reactive B cells capable of mediating heterosubtypic protection. This proposal seeks to investigate the processes regulating the development, maintenance, and reactivation of influenza-specific lung-resident memory B cells. This goal will be accomplished in two specific aims: 1) Investigate the mechanisms underlying B cell migration to and maintenance within the lungs and; 2) Explore the requirements for memory B cell reactivation within the lungs and their contribution to long- term protective immunity. The proposed research will significantly increase understanding of how lung-resident memory B cells develop and function with the long-term goal being to harness this knowledge to design vaccines better able to elicit these cells. This work will provide a foundation for future R01 applications centered on the contribution of resident memory B cells to protective immunity in settings of disease.